Effect of Y 6 , an epigallocatechin gallate derivative, on reversing doxorubicin drug resistance in human hepatocellular carcinoma cells

// Yan Wen 1, 2, * , Rui-Qiang Zhao 2, 3, * , Yun-Kai Zhang 2 , Pranav Gupta 2 , Li-Xiang Fu 4 , An-Zhou Tang 5 , Bu-Ming Liu 6 , Zhe-Sheng Chen 2 , Dong-Hua Yang 2 , Gang Liang 4 1 Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, P.R. China 2 2Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA 3 Department of Biochemistry and Molecular Biology, School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, P.R. China 4 College of Pharmacy, Guangxi Medical University, Nanning 530021, P.R. China 5 Department of Otolaryngology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, P.R. China 6 Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Guangxi Institute of Chinese Medicine and Pharmaceutical Sciences, Nanning 530022, P.R. China * These authors contributed equally to this work Correspondence to: Gang Liang, email: lianggang0922@foxmail.com Dong-Hua Yang, email: yangd1@stjohns.edu Keywords: Y 6 , epigallocatechin-3-gallate (EGCG), multidrug resistance, resistance reversal agent, doxorubicin Received: January 16, 2017      Accepted: February 12, 2017      Published: March 07, 2017 ABSTRACT Cancer cells can acquire resistance to a wide variety of diverse and unrelated drugs, this phenomenon is termed multidrug resistance (MDR). Multidrug resistance has been an obstacle to the success of cancer chemotherapy. The present study investigated the reversal effect of Y 6 , a new compound obtained by chemically modifying the structure of epigallocatechin-3-gallate (EGCG) extracted from green tea. Y 6 was proven to be effective in inhibiting cell proliferation and reversing drug resistance in doxorubicin (DOX) resistant human hepatocellular carcinoma cells (BEL-7404/DOX). BEL-7404/DOX cells were treated with either doxorubicin combination regimen (doxorubicin plus Y 6 or epigallocatechin-3-gallate or verapamil separately) or doxorubicin alone. The results showed that cell proliferation was inhibited and late cell apoptosis increased in the combination treatment group, especially in the group treated with doxorubicin plus Y 6 . Further analysis revealed that the expressions of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein decreased at both messenger RNA and protein levels by treatments with combined drugs compared to doxorubicin alone. Our results indicated that Y 6 , as a drug resistance reversal agent, increased the sensitivity of drug resistant cells to doxorubicin. The mechanisms of actions of Y 6 in reversal effect were associated with the decreased expression of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein.